Advanced kidney cancer (renal cell carcinoma, RCC) is a devastating disease, with a 5-year survival of 8% in patients diagnosed with Stage IV RCC. While newer therapeutics such as kinase inhibitors have been approved during the last decade and checkpoint inhibitors more recently, these agents rarely result in durable responses, with cancer cells persisting in the patient during treatment, or after treatment when the patient is in remission. These surviving cancer cells are clinically called residual disease, which is the primary cause of relapse and death in cancer patients. Therefore, developing effective therapies to combat residual disease represents an important unmet clinical need. Clinically, residual disease presents a complex and perhaps mixed set of mechanisms that involves cell autonomous and microenvironment factors, but ultimately these can be distilled to a singular, unifying purpose: to marshal the nutrient uptake required to meet the cancer cell's unrelenting metabolic demands for growth. Surprisingly, relatively little is known about the signals that drive metabolic uptake during cancer treatment. Autophagy occurs at a basal rate in most cells to maintain cellular homeostasis by degrading protein aggregates and damaged organelles. Cancer cells increase autophagy to supply nutrients required for their growth. Paradoxically, cancer therapies also increase autophagy which contributes to chemoresistance, tumor survival and ultimately, residual disease. However, the metabolic adaptations conferred by treatment- induced autophagy and how this fosters resistance and consequently, residual disease are unknown. By co-targeting a metabolic and oncogenic pathway, we have identified a combination that overrides autophagy-mediated metabolic reprogramming in advanced RCC. The goal of this project is to deconstruct the mechanism by which treatment-induced autophagy enables cancer cells to survive. This will be accomplished through repurposing of cardiovascular drugs as cancer therapies, metabolomics and genomic profiling in preclinical models and by validating our findings in patient samples. These studies will not only provide invaluable preclinical data to guide the development of a clinical trial, but will uncover mechanisms that kill RCC cells, which may ultimately lead to the development of improved therapeutic strategies for this devastating disease.